Cache:7kkfat7zlhwj:surpe5.xe.cx qcyd by impositive fungus

I've posted this in the discord with some limited, but helpful feedback. Hoping to maybe get some different/additional thoughts here. Some of this is long so I've double bracketed the TL;DR if that's more enticing. Though if you're inclined, the details may matter?
1: What do you desire? What is your end goal?
[[ The freedom to pursue my hobbies and indulge my curiosity at my own pace, while still reasonably maintaining my familial responsibilities. ]]
This is tricky for me. Truthfully, I don’t really have some sort of real end goal or master plan for my life, I’m more or less just… persevering and trying to keep on keepin’ on. In terms of what I desire, I really would love to live a life without undue imposition. I would love to get to a place where my obligations are ones that I mostly take on intentionally, rather than feel like I’m being saddled with the innumerable responsibilities of living in the world today. Maybe this is impossible, I don’t know. I am often a path of least resistance kind of guy. I also strongly desire the freedom to pursue my hobbies/interests, which include consuming and creating stories, intentionally raising my child (soon to be children), and learning more about the world we live in.
2: What means do you use to achieve these ends?
[[ Carve out what little time I have each day for hobbies, without shirking my family or the (unfortunate) necessity of making a living. ]]
This one is also quite tricky. I think my answer is… mostly nothing? At least in terms of creating a life free from obligation. I’m a father of a toddler (with one more on the way), and I work a job that pays too little, strapped with debt, and crunched for time. We’re making it work just fine, but I’m certainly far from any kind of temporal freedom that I might desire. I often feel listless, and don’t have a strong sense of ambition. I am a teacher, and that certainly affords me opportunities to continue my quest for knowledge. I also spend a lot of time consuming new stories in the forms of TV, movies, books, games, Podcasts, etc. I express myself through my art and creating stories/characters for a few DnD campaigns I belong to. I don’t know if I’m answering the question, but I suppose I am just doing my best to use what little free time I have in the pursuit of knowledge and creative expression/consumption. I would love to say that I am actively working toward improving my financial situation in a way that can afford me more freedom, but I would be lying.
3: What do you care about? What values are important to you?
[[ I want to be constantly learning/absorbing new things. Protecting the innocent/downtrodden is a primarily important concept to me, whether or not I am the one personally doing the protecting. ]]
I care a lot about learning new things, especially about society and the natural world. I studied anthropology in my undergrad, moreso for personal knowledge than any concrete career path. I am an avid lover of nature and enjoy learning about plants, animals, fungus, and natural processes in general. I don’t necessarily need to be accumulating functional knowledge that will help me progress on some sort of grand path, I just love learning new things for the sake of it (I’m also pretty decent at/enjoy bar trivia). As a teacher and father, I am also very invested in the wellbeing of children, especially young ones, with whom I work. Helping to guide young minds, and leave them better off than when I met them is a very gratifying and important part of my life/job, even if it is as simple as changing their opinions about bugs or fostering their artistic abilities.
4: What do you despise? What negatively drives you?
[[ Personally, I hate being unduly imposed upon. On a wider scale, I truly abhor abuses of power, especially on a systemic level. From corrupt cops, to predatory corporate structures, to colonialism. The root of all evil. ]]
Firstly and simply, I hate being told what to do. It’s silly, and perhaps juvenile at times, but I really don’t like being imposed upon unless it makes sense to me (like deferring to a reasonable boss at work, or listening to the advice of a respected mentor). More importantly, the wanton desire for, and gross accumulation of wealth/resources boggles my mind and boils my blood. There is so much waste, and so much hoarding in the world. I believe that the existence of billionaires alone is a moral failing of our society at large. Those in positions of extreme wealth/power who leverage their status to only improve their own lives, at the detriment of others, makes me furious and hopeless. The existence of multibillion dollar corporations that pillage our society and natural world for profit also falls into this bucket of rage. Similarly, those who take advantage of or harm children also destroy me. Even in the small ways in which parents set their children up for social/emotional/academic failure by either being terrible examples or through obviously outright abuse. The latter points in particular drive me to be the best father I can reasonably be. I have seen the results of poor parenting (both benign and severe) very intimately over the course of my 12 year career, and it saddens me to no end to witness innocent and impressionable children put down a negative path that they have no control over.
5: What ideals do you appreciate but don't get; what values do others hold that you hate?
[[ 5a: I can admire those who are (rationally!) spiritual, even though it’s not something I can personally get behind. 5b: I really dislike the emphasis that many put on social status, either of themselves or admiration of the social status of others. Celebrity worship is awful. ]]
5a: While I view “big religion,” from a historic perspective, as being a social detriment in a lot of ways (see the above points regarding abuses of power), I am often envious of those who find spiritual meaning in the world. I don’t really wish I were religious or spiritual, as it all feels like pretending to me, but I have no ill will toward those who have that deep feeling of spiritual belonging to the world/universe/whatever. I’ve had fits and starts in my younger days, but right now it just feels…fake. That’s honestly fine, as I believe in the power of belief, and that people create their own meaning, and as long as you’re not hurting anyone you can believe that Jesus was an interdimensional alien who was sent to help us transcend to the 5th dimension or whatever. I just can’t bring myself to that point, or any point like it. We are random electrical bags of water and meat that are alive by mistake. And that is cool and fine too!
5:b I hate (or more accurately just really irked by the fact) that some people care so much about social status. This is linked to the points about the accumulation of wealth and power, but also regarding things like celebrity worship and aggrandizement of excess. Who cares?! Over-conformity and insistence on formality also bugs me (see the previous statement about being told what to do). I’m not going to be an asshole about wearing a suit to a wedding if that is what is requested, but I do roll my eyes at dress codes and stuffy cultural expectations of dress. Again, imposition on my freedom. I want to be free to CHOOSE to gussy up for an event!
6: What is your greatest strength and biggest weakness?
[[ 6a: I am a pretty adaptable jack of all trades. 6b: I have no real drive or ambition, and am a chronic procrastinator. I also have a hard time being outwardly sincere with others. ]]
6a: I see myself (or perhaps would LIKE to see myself) as a fairly adaptable and flexible jack of all trades. I’m a pretty smart guy in various domains, a decent artist (in my own lane of doodling and creative writing), fairly handy around the house, not completely out of shape, and have a solid mental/emotional/physical fortitude. Not outstanding in any of those fields, necessarily. In my professional life I wear a lot of hats and am able to roll with the punches quite well. I’d like to think that I can use this generalized skillset to creatively and practically solve diverse problems, and I quite enjoy doing so.
6b: My biggest weaknesses are definitely procrastination and a lack of ambition. I do what I’m good at, but rarely venture further into major life changing endeavors due to a fear of the negative emotions surrounding potential failure. I’m trying to expand into a growth mindset, but it’s tough. I also have a very hard time being sincere or genuine. Not that I feel negatively about most things/people necessarily, but I have a hard time tapping into the emotional center required to genuinely express gratitude. It’s like there is a psychic wall pushing back on me. It’s another silly and immature thing, but it makes me feel weird and bad to be overtly wholesome and deepen emotional connections with peers.
Thank you!

Happy New Year All. Now that CytoDyn is over the clinical hold, 2024 should pan out to be an amazingly successful year proving that leronlimab lowers the rate of inflammation and increases the rate of proliferation in patients living with HIV.
The following may help as a preface in the understanding of the following, but may not be necessary. Let's try to put it all together.
Macrophage Activation: Macrophages can be activated in 2 ways: The Classical Pathway and The Alternative Pathway. Inactivated Macrophages wait around for a chemical signal to activate them. Initially, their first purpose is to address the diseased situation, to enable the body to clear out the diseased tissue first and then once fully cleared of the disease and the tissue prepared, then secondly, the repair of that tissue may take place.
M1 Activation: Whenever microbes or Interferon Gamma stimulate the Macrophage, the Macrophage becomes Activated in the Classical Pathway and becomes an M1 Macrophage. Interferon Gamma is liberated by T Helper 1 cells when faced with a pathogen. The same Microbes and Interferon Gamma while Activating the Classical Pathway which is the Pathway for destruction and breakdown are simultaneously inactivating the Alternative Pathway which is the Pathway for healing and vic-versa.
The Classical Pathway M1 Macrophage results in the production of Reactive Oxygen Species (ROS), Nitric Oxide (NO), Lysosomal Enzymes and all of these things which have a Microbicidal effect. The M1 Pathway leads to a lot of Interleukins: Interleukin 1 (IL-1), Interleukin 12 (IL-12) and Interleukin 23 (IL-23) which all have a role in inflammation.
M2 Activation: When the Macrophages are Activated in the Alternative Pathway, they will have been induced there by Interleukin 13 (IL-13) and Interleukin 4 (IL-4) which are both liberated by T Helper 2 cells once the initial stage is complete and the area is prepared for repair. As stated above, IL-13 and IL-4 when present, inactivate the Classical Pathway.
In the M2 Alternative Pathway, growth factors are liberated such as Transforming Growth Factor Beta (TGF Beta) which results in Repair and Fibrosis. The liberation of Interleukin 10 (IL-10) results in Anti-Inflammatory effects.
Both Acute and Chronic Inflammation requires Macrophages, Lymphocytes, Plasma cells and Mononuclear cells. Inflammation must first M1 break down and clear away the sick and injured connective tissue via neutrophil release of proteolytic enzymes (ROS & NO) that break down the tissue into debris. Then it allows for the M2 healing of that tissue. Angiogenesis and Fibrogenesis. M1 Inflammation leads initially to Tissue injury, destruction and necrosis. Once the sick and injured connective tissue is cleared away, then, M2 attempts at wound healing are made with Angiogenesis which is the formation of new blood vessels. This leads to granulation and re-epithelization. Macrophages in the M1 state transform into M2 Macrophages aka Fibroblasts which release collagen fibrils that bridge tissue together thereby creating scar tissue which leads to Fibrosis and Scarring, tissue remodeling and eventual healing.
Macrophages were originally monocytes, but when they leave the endothelial cell and then subsequently enter the tissue they were called to, they transform into and become Macrophages. These WBCs initiate connective tissue repair and secrete inflammatory mediators. They display antigens to T Lymphocytes. They respond to signals from T Lymphocytes. CD4 and CD8 Lymphocytes. Liver Macrophages are called Kupffer Cells. Central Nervous System Macrophages are called Microglial Cells. Macrophages in the Lungs are called Alveolar Macrophages. Macrophages in the spleen and Lymph Nodes are called Sinus Histiocytes.
In the proposed clinical trials, we are dealing essentially with Chronic Inflammation. This is the response of a prolonged duration, (months to years) in which M1 inflammation, tissue injury/destruction and M2 attempts at repaihealing of the connective tissue coexist in varying quantities and combinations. Since M1 inflammation, tissue injury and M2 repair are all happening together simultaneously and are in various states and levels of progression and in various combinations and degrees of completion, there will be both elevated levels of certain cytokines which promote connective tissue breakdown & destruction and elevations of other cytokines which promote and enable connective tissue healing. 3 things are happening simultaneously. 3 things coexist. Connective Tissue destruction, Connective Tissue Repair and Inflammation.
It should be noted that Parenchymal tissue, (Internal Organ tissue), is not metabolized for the purposes of regeneration by the Macrophages and is also not regenerated by the Fibroblasts. The only organ which can be regenerated is the Liver and it only does so as a compensatory function for what the needs of the body dictate. Could it be possible that MASH exists because of the fact that the liver is the only organ capable of regeneration, despite it only being a compensatory regeneration? Otherwise, the liver would just have sickened, became necrotic and died, along with the patient. We can make the analogy that MASH is akin to a patient living with chronic HIV disease for years and years because in MASH, the liver is dealing with chronic Immune Activation and Chronic liver injury whereas in HIV, the patient is dealing with the effects of Chronic Immune Activation and chronic system wide injury causing chronic system wide repair of afflicted tissues and systems.
In Liver Cirrhosis, with repeated iterations of liver regeneration, and after years of MASH, the normal lobular architecture of the liver is lost, and it is replaced by Regenerative Parenchymal Nodules that are separated from each other by irregular bands of Fibrosis and varying degrees of vascular Portal Vein shunting.
See the images in the following for better clarity in the text that follows. Interpretation of NASH Trial The hepatic sinusoid is lined by endothelial cells. The space between the endothelial cell and the underlying hepatocyte is called the space of disse, perisinusoidal space. There are hepatic Stellate cells in the space of disse. The hepatic Stellate cell has an important role in the pathogenesis of liver cirrhosis because these cells are responsible for fibrosis. When the hepatic Stellate cells are inactive, they function as lipid storing cells. When these Stellate cells get activated following liver injury, then, they are transformed into myofibroblasts. Myofibroblasts are fibrogenic. They help to produce fibrosis.
Summarizing: Liver Cirrhosis occurs because of persistent liver injury in an organ capable of regeneration. Initially, the liver goes through increasing degrees of MASH and the last and final stage is Liver Cirrhosis which also can lead to HepatoCellular Carcinoma (HCC). Long time liver injury causes death of liver cells or Hepatocytes. However, at the same time, there are other hepatocytes that are surviving the injury. Those surviving hepatocytes, (unlike in all other organs), have a remarkable ability to replicate and multiply. It is these replicating hepatocytes that are responsible for the regenerative parenchymal nodules. The hepatic Stellate cells located in the space of disse, once becoming activated, becomes transformed or converted into myofibroblasts (myo contractile, fibrogenic), which are responsible for the contractile fibrosis which holds together the regenerative parenchymal nodules.
Fibrosis is the excessive deposition of collagen and extra-cellular matrix components into a tissue. The Extra-cellular matrix (ECM) is a collection of various extra-cellular molecules which are usually secreted by different types of cells and this collection of extra-cellular molecules outside the cell is responsible for the structure of the support and various bio-chemical functions outside the cell. The ECM always contains a basement membrane and interstitial spaces. This makes up the ECM. Scarring and Fibrosis terms are used interchangeably. Fibrosis can be associated with tissue loss.
Causes of fibrosis. Persistent Injurious Stimuli, Chronic Infection, AutoImmune Reactions such as Rheumatoid Disease, Sarcoidosis, Lupus, etc and Trauma. Healing either occurs by Regeneration (which only happens in the liver), or by repair via deposition of connective tissue (which happens everywhere else and also including the liver as well), where scars can be formed in the deposition of connective tissue. Regeneration is when the damaged/necrotic tissue is replaced with similar type of cells and when the damaged tissue is returned back to its original state of functionality. This is regeneration. Damage to non-dividing cells can not result in regeneration. In that case, when non-dividing cells are damaged, regeneration is not possible. Therefore, in such cases, the body does a "patch work" and deposits connective tissue instead. This is when we will see scar formation.
Scar tissue requires angiogenesis because in order to drive the deposition of collagen, a blood supply is necessary and so angiogenesis occurs. In order for angiogenesis to occur, Vascular Endothelial Growth Factor (VEGF) is necessary. Granulation tissue occurs due to the migration of fibroblasts. Fibroblasts migrate and proliferate at the site of injury and release loose connective tissue. Fibroblasts, loose connective tissue, ECM components, new blood vessels, Inflammatory cells like Macrophages will all be present.
Remodeling of the Scar; Remodeling of the connective tissue. MMPs break down connective tissue. This concept introduces the role of Matrix MetalloProteinases (MMP). This is a very important enzyme responsible for the degradation of collagen and other ECM components. MMPs are a family of enzymes produced by a variety of cells which are responsible for the degradation of various ECM components. Metalo...these enzymes are dependent upon metal, mainly upon zinc. MMPs will be upregulated during M1 to break down fibrotic scar tissue and to break down connective tissue. MMPs are also necessary during M2 to remodel the scar tissue. MMPs are produced by Fibroblasts, Macrophages, Synovial cells, Neutrophils and Epithelial cells. Usually, MMPs are produced in their inactive form and when needed, they can be activated. MMPs includes interstitial collagenase which degrades fibular collagen, MMP 1,2,3 all degrades fibular collagen.
The Persistent Injurious Stimulus due to infection, disease or trauma, results in the Activation of Macrophage and leucocytes. In the Repair mode, Macrophages are M2 Macrophages in the Alternative Pathway during Repair. Here, the Macrophages are Activated in the Alternative Phase of Activation. The M2 Macrophages liberate many growth factors including Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF) and Transforming Growth Factor Beta (TGF Beta). These growth factors have a role in the proliferation of Fibroblasts, Specialized Fibrogenic Cells and Endothelial Cells. End result is formation of collagen and more ECM components. In addition, Activation of M2 Macrophages leads to the liberation of Cytokines such as Tumor Necrosis Factor (TNF), Interleukin 1 (IL-1), Interleukin 4 (IL-4), Interleukin 13 (IL-13) all of which help production of collagen synthesis. When M2 Macrophages are activated, MMP activity is reduced so that collagen is not degraded, but rather leads to increased fibrosis.
Inflammation induces Adhesion such that the Macrophages have the capacity to stick to the appropriate cells/tissues upon which they need to act. In general, Inflammation creates an adhesive environment, such as in Frozen Shoulder or in Adhesive Capsulitis and also conditions such as NASH with a scarring Fatty Liver. Most pathology ends in "...itis" which indicates "inflammation of". For example, Hepatitis is inflammation of the Liver, Pancreatitis is inflammation of the Pancreas.
With regards to inflammation, Adhesion is mediated by proteins named Integrins, which are expressed on the surface of the WBC and on the endothelial surface. The endothelial surface is the surface of the endothelial cells. Endothelial cells form a single cell layer that line all blood vessels and regulate the exchange between the bloodstream and the surrounding tissues. Signals from endothelial cells organize the growth and the development of connective tissue cells which form the surrounding layers of the blood-vessel wall.
The (2) Biomarkers which can be used to "measure or quantify" the level of Adhesiveness that is going on which is proportional to the level of inflammation a patient is experiencing at a given moment, is ICAM and VCAM. ICAM is Intercellular Adhesion Molecule and VCAM is Vascular Cellular Adhesion Molecule. When endothelial expressed VCAM or ICAM attach to the respective receptors on the leucocyte WBC, these leucocytes stop moving, stop rolling and become firmly fixed to the endothelial cell and then may be subsequently transferred to the tissue requiring the WBC.
Activating Macrophages:
Two Major Pathways: M1 Classical Pathway and M2 Alternative Pathway
M1 Classical Pathway: Microbicidal Actions, Inflammation
M2 Alternative Pathway: Connective Tissue RepaiHealing, Anti-Inflammatory Effects
The presence of Interferon Gamma leads to or Induces the Classical Pathway M1 Macrophages. M1 Macrophages produce Reactive Oxygen Species, (ROS), Nitrous Oxide (NO), Lysosomal enzymes, Interleukin 1 (IL-1), Interleukin 12 (IL-12), Interleukin 23 (IL-23) leading to Inflammation. All of these may be elevated in Acute Inflammation, but Interferon Gamma would have been elevated initially, as that cytokine would have converted the inactive Macrophage into the bactericidal M1 state.
The presence of Interleukin 13 (IL-13) and Interleukin 4 (IL-4) leads to or Induces the Alternative Pathway to M2 Macrophages. M2 Macrophages produce Transforming Growth Factor Beta (TGF-Beta), Interleukin 10 (IL-10). Angiogenesis, Collagen Synthesis, Stimulate Fibroblasts that release collagen fibrils, Connective Tissue Repair, Fibrosis, Anti-Inflammatory Effect. Both IL-13 and IL-4 initially converts M1 Macrophages to M2 Macrophages leading to tissue healing and anti-inflammatory, proliferative effects.
Other cells of Chronic Inflammation: Lymphocytes, Plasma Cells (B Lymphocytes which produce antibodies), Eosinophils (allergy, parasitic infection), Mast Cells (degranulation releases histamines), Neutrophils (Chronic Osteomyelitis, Chronic Lung Damage).
Cytokines Involved in Inflammation
In Acute Inflammation
Tumor Necrosis Factor (TNF) Produced by Activated Macrophages, Mast Cells & T Lymphocytes; Endothelial Activation is Induced; Increased Integrins, Increased Adhesion; For Fibroblasts, TNF increases Proliferation of Fibroblast and increases Collagen Synthesis from Fibroblasts; Leucocyte Activation, Neutrophil Activation, Macrophage Activation with help of NO. So, TNF & NO may both be elevated in both M1 as well as M2 states.
Interleukin 1 (IL-1) is Produced by Activated Macrophages, Endothelial Cells and Epithelial Cells; Endothelial Activation is Induced; Increased Integrins, Increased Adhesion; For Fibroblasts, IL-1 increases Proliferation of Fibroblast and increases Collagen Synthesis from Fibroblasts; Leucocyte Activation, Neutrophil Activation, Macrophage Activation with help of NO. So, IL-1 & NO may both be elevated in both M1 as well as M2 states.
Some Acute Phase Reactants are increased with TNF and IL-1. They are CRP, Fibrinogen and Serum Amyloid A. Interleukin 6 (IL-6) IL-6 has a role in the production of Acute Phase Proteins like CRP and Fibrinogen. IL-6 is responsible for the production of these Acute Phase Reactants. IL-6 has a role in the production of acute phase proteins like CRP and Fibrinogen. Fibrinogen is necessary in the production of Fibrin, collagen fibrils which bridge the gaps in the connective tissue.
Interleukin 17 (IL-17) Produced by T-Lymphocyte, IL-17 recruits Monocytes and Neutrophils to the site of inflammation. Involved in both Acute and Chronic Inflammation.
Chemokines: Chemoattractants for WBCs Lymphocytes which are necessary for the Recruitment of leucocytes to the site of inflammation.
In Chronic Inflammation, there is the Combination of both long-term prolonged Inflammation and long-term anti-inflammation or Proliferation
Interleukin 12 (IL-12) Produced by Macrophages and Dendritic Cell; IL-12 major function is to increase production of Interferon Gamma. Interferon Gamma Activates Macrophages. Even though they are Killer Cells, they are not always in a Killing Mode. That mode would be an inactive mode. But, with the presence of Interferon Gamma, they become Activated into a Killing Mode. M1 Macrophage becomes a pumped-up killing machine which kills bacteria, virus, fungus, mold and cancer.
Interleukin 17 (IL-17) Produced by T Lymphocyte. Neutrophils and Monocyte Recruitment to the site of inflammation. Involved in both Acute and Chronic Inflammation
Interferon Gamma (IFN-Gamma) Cytokine that Activates Macrophages; Produced by T-Lymphocytes and Natural Killer Cells. Transforms inactivated Macrophages into Activated Macrophages.
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Monocyte Chemotaxis: Chemokines, TNF, Platelet Derived Growth Factor (PDGF), FibroBlast Growth Factor (FGF), Transforming Growth Factor Beta (TGF-Beta)
Fibroblast Migration: PDGF, Epidermal Growth Factor (EGF), FGF, TGF-Beta, TNF, IL-1
Angiogenesis: Vascular Endothelial Growth Factor (VEGF), angiopoietins, FGF
Collagen Synthesis: TGF-Beta, PDGF
Collagen Secretion: PDGF, FGF, TNF, TGF-Beta inhibits
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So, the question is whether the upcoming trial shall be a Phase IIA or a Phase IIB trial.
I think this shall be a trial that transitions from Phase IIA to Phase IIB to Phase III.

"00:03:45, Dr. Jacob Lalezari:
I'm also excited to announce that CytoDyn submitted a new Phase II protocol to the FDA to evaluate the effects of 24 weeks of leronlimab on chronic immune activation and inflammation in cisgender men and transgender women living with HIV*. This protocol was submitted in early November alongside the company's response to the partial clinical hold. Chronic immune activation and inflammation cause strokes, heart attacks, and other vascular events and remain the leading cause of death in people living with HIV. The FDA letter of November 30th, in addition to lifting the partial clinical hold, also provided extremely helpful guidance on* CytoDyn's proposed immune activation protocol in order to help optimize our chances of success while taking aim at this complicated therapeutic challenge and critical unmet need.
00:04:45, Dr. Jacob Lalezari:
Now, to be clear, CytoDyn was again placed on a new clinical hold for the immune activation study while we incorporate FDA feedback and prepare a revised protocol. I want to stress that this new clinical hold is often a normal part of the FDA review process on newly submitted protocols. The hold does not raise any new regulatory or safety concerns and it will be removed after we respond to FDA's guidance concerning our protocol design, primary and secondary endpoints, and stopping rule. We're reviewing the FDA guidance now with our key consultants and expect to submit our revised protocol in January.
00:05:40, Dr. Jacob Lalezari:
So, just to summarize and be clear, the partial clinical hold over the last 22 months has been removed and all past issues have been completely addressed. We expect the new hold to be lifted after we incorporate FDA's recent suggestions and submit our revised immune activation protocol in January. After that resubmission, the FDA will have 30 days to respond to comments. I know that the simultaneous removal of one hold and the imposition of a new hold can seem confusing. But I want to assure everyone today that this is all very good news for CytoDyn, and we are excited to be turning the page and moving forward."

So, from the above, the proposed clinical trial shall be a Phase II Protocol clinical trial.
What about dosing? The following discusses the use of (2) doses, 350mg and 700mg as well as placebo.

"00:24:03 Dr. Jay Lalezari:
And the consensus with the HIV consultants has been that we look, go circle back to HIV, but instead of looking at leronlimab as an antiviral, we are looking now at leronlimab as a modulator of immune activation*. Is that a relevant endpoint? It is, because* immune activation inflammation is the primary driver of mortality in HIV patients*. Strokes, heart attacks, liver, kidney. It is unfortunately a* much more difficult endpoint to assess than simply following an HIV viral load, but it is kind of in the wheelhouse of what we're believing leronlimab is capable of*. So the proposed next study is to look at leronlimab in HIV positive ambulatory subjects. We know it's safe in that group. In* individuals who demonstrate elevations of immune activation markers. So known evidence of immune activation inflammation. And then we're tentatively looking at both doses 350 and 700mg and looking at a nested placebo arm so that at the end of 24 weeks of treatment, we can at least get a real measurement of whether leronlimab has moved the needle there or not.

Cohort? Half will be transgender women and the other half cisgender men who are both positive for HIV, and who both have elevated activation markers at the beginning of the trial.

00:25:36 Dr. Jay Lalezari:
I think that's a study that the FDA is going to have a hard time not wanting to see done. There is currently no therapy for immune activation in HIV. Half the patients we're going to enroll are going to be transgender women who have elevated activation markers because of the hormonal therapy they're taking. And in fact, what I had mentioned earlier was that the FDA, having received the protocol, has asked if they can cross-reference the IND file for NASH, which is exactly the right question to be asking is “what other evidence do we have that leronlimab is mediating inflammation and immune activation?”. So that we are waiting to hear."

​
Is there enough drug?

"Marta:
Thank you. What is the status of a manufacturing partner and their relationship with Samsung?
Dr. Jacob Lalezari:
I'll just say that one of the things I've been working on is to make sure leronlimab has enough drug to do the study that we're proposing*.* It would be a good problem to launch this study, enroll it, and have enough positive outcomes that we need more drug. But that is not going to be. Antonio, do you want to speak to that?"

​

"00:35:25 Tyler Blok:
Then I can actually... Yeah, yeah, yeah. So, Hi Marta. Tyler here again, company counsel. Tyler Block. I imagine this question somewhat came up due to the recent AK filing disclosure about the relationship with Samsung. So, the long and the short of it is we're in prolonged negotiations with Samsung. It represents a significant and substantial past due balance rate. It's a very large financial commitment if and when we're able to resolve it with Samsung. So, what we're evaluating in our approach to the Samsung relationship is we're considering a couple of variables, but one of which is that we do, in fact, currently hold enough leronlimab to complete the contemplated clinical trials in both the short and the long term short and mid-term that the company would have. So with that in mind, we are evaluating, okay, what's the perspective future manufacturing needs and which third parties make sense to work with. Because at the end of the day, we don't exclusively manufacture with Samsung and we have options in that regard. So while we have a vested interest in resolving the situation with Samsung, we're going to do it if and when it makes sense for the company to reach a resolution with Samsung. And then as Jay alluded to earlier, in the short term, we do have enough leronlimab to complete the contemplated trial. So while Samsung recently notified us that they intend to terminate the agreement in January, that is viewed, for the most part, as a negotiating tactic and really trying to get us to the table. So we're working with their counsel. We intend to continue the negotiations. But for right now, we're not in a panic as it relates to Samsung.

So, there will be sufficient quantities of leronlimab to complete the Phase IIA and Phase IIB trials, but if this trial is successful and warrants a Phase III trial, new product will need to be manufactured to supply the Phase III trial. As Dr. Lalezari says above, "It would be a good problem to launch this study, enroll it, and have enough positive outcomes that we need more drug."
Now, this is my opinion. I'm thinking that if the endpoint becomes only one or two or a just a few specific Biomarkers which do not reflect the entire situation as a whole, then it might become a futile pursuit. I'm thinking that the whole state of inflammation is better represented and captured by the cumulative effect of many Biomarkers that are strategically combined into one formula or into an equation. That equation might output a number or a value which the level of, depicts or communicates the cumulative inflammatory or proliferative effect of what is happening in that patient. That number should actually measure and capture the state of inflammation or proliferation in that patient. I believe that this is what shall be necessary, but again, this is all my opinion. Who knows, there may in fact be one specific or two or three Biomarkers which alone may correctly indicate the state of inflammation / proliferation and immune activation, but I'm thinking many Biomarkers combined in an equation that weighs their significance will be required.
Since I believe the solution becomes a certain combination of strategically chosen variables arranged and weighted into what I suspect might be an AI derived equation, I'll list the Cytokine variables that had an effect on inflammation which was provided in the Heat Map in the EASL Poster. The importance of VCAM, ENRAGE, Age of Patient, Years on ART therapy, Number of Thromboemboic Events in the Past, (DVT's, PE's, TIAs, Strokes, MI, etc...), as well as the Cytokines and Interleukins mentioned here are likely candidates to be inputs of this equation.
Since we know that in HIV, as a result of the patient's already relatively weakened immune state, the immune system is therefore constantly activated just like the liver is constantly Activated in MASH and in Cirrhosis. In both cases, pathogens and antigens are not fully eradicated from the body or from the liver because the immune system is too weak to be 100%, efficient. Therefore, these pathogens persist within the body and liver serving to constantly activate and stimulate the immune system indefinitely. This is the Chronic Immune Activation in these patients living with HIV as well as in MASH patients. This means that in general, in the case of patients living with HIV and also in patients with MASH and Cirrhosis, Inflammation will always exist and that the rate of inflammation progression will exceed the rate of proliferation. Inflammation will always be a step ahead in these patients without leronlimab.
​
For example, in the following: OBESITY AND WEIGHT GAIN IN PERSONS WITH HIV the accumulation of steatosis or fat on the liver in patients with MASH. This can be correlated to the development of cardiovascular disease (CVD) in people living with HIV.
"PWH are at increased risk for cardiovascular disease (CVD) including myocardial infarction, stroke, and atherosclerosis [116–119]. In a recent systematic review, the pooled risk ratio for CVD was over 2-fold greater in PWH compared with HIV-negative individuals, and the global burden of CVD in PWH increased between 1990 and 2015 [119]. While traditional risk factors such as male gender, older age, diabetes, hypertension, and race are associated with CVD [117], PWH have elevated risk relative to HIV-negative even after adjusting for demographic characteristics, Framingham risk factors, comorbidities, and viral suppression [120]. ART exposure [116], systemic inflammation [121], reduced arterial elasticity [122], and endothelial dysfunction [123], may contribute to excess risk of CVD in PWH. In the SMART trial, PWH with the highest quartile of IL-6 had a hazard ratio of 4.65 for CVD compared with individuals in the lowest quartile, and this was independent of other predictors of CVD [121]. Central adiposity is associated with other predictors of cardiovascular disease in PWH [39], and ectopic adipose deposition has been associated with CVD in both PWH and HIV-negative [76, 77, 124]. "
​
However, most patients with these conditions are in somewhat of a steady state and may exist in such steady state conditions for years. Therefore, we can make a generalized equation of:
(Rate of Inflammation) - (Rate of Proliferation) = (Inflammation Score)
If the Inflammation Score is positive, the patient is in an Inflammatory State
If the Inflammation Score is negative, the patient is in a Proliferative State.
If the Inflammation Score is about zero, then, in a steady state situation.
​
Where:
(Rate of Inflammation)
ENRAGE + RANTES + Tissue Inhibitor of MetalloProteinase + TNF + VCAM + ICAM + Interferon Gamma + IL-1 + IL-3 + IL-6 + IL-7 + IL-8+ IL-12 + IL-17 + IL-23
and
(Rate of Proliferation)
MMP3 + MMP9 + VEGF + TNF + VCAM + ICAM + IL-1 + IL-2 + IL-4 + IL-5 + IL-6 + IL-10 + IL-13 + IL-17 + Platelet Derived Growth Factor (PDGF) + Fibroblast Growth Factor (FGF) + Transforming Growth Factor Beta (TGF Beta) + Epidermal Growth Factor (EGF)
​
by eliminating the duplicated Biomarkers, the equations become:
(Rate of Inflammation)
ENRAGE + RANTES + Tissue Inhibitor of MetalloProteinases + Interferon Gamma + IL-3 + IL-7 + IL-8 + IL-12 + IL-23
and
(Rate of Proliferation)
MMP3 + MMP9 + VEGF + IL-2 + IL-4 + IL-5 + IL-10 + IL-13 + PDGF + FGF + TGF Beta+ EGF
​
Either the rate of inflammation or the rate of proliferation may be necessary to be scaled to be equalized with the other rate by the determination of this scaling factor X in a good number and good variety of healthy patients that are not living with HIV to obtain the appropriate scaling factor X, such that when:
(Rate of Inflammation) - X(Rate of Proliferation) = 0.
The equation may also need to take into consideration the starting age of the patient, the number of years on ART therapy. The Number of Thromboemboic Events in the Past, (DVT's, PE's, TIAs, Strokes, MI, etc...) before entering the trial. Maybe the scaling factor X needs to change based on patient Age for instance.
It could turn out that values from (-10 to 10) are considered normal.
Values from (-25 to -10) are considered Pre-Proliferative and Values from (10 to 2) are Pre-Inflammatory
Values below -25 could be considered Proliferative and Values exceeding 25 could be considered Inflammatory.
Then these could be compared to before and after treatment.

[←Chapter 25] [Cover Art] [My Links] [Index] [Discord] [Subreddit] [Chapter 27→]
For the first time in days, Aya had managed to stop trembling. Everything that’d led up to this point - the flight from her village, the attack on her mother and herself, being taken away to some far off place she’d barely heard of, the second attack…
All of it had sunk deep into her bones, leaving her a shaking mess, barely able to talk without teeth chattering. But as she took Frare’s hand, the one not stained by whatever blood the monster possessed, she felt something pass through her. Calling it a wave might’ve been too violent - it was more like a ripple, leaving calm water behind it as it passed.
She was yanked to her feet, the movement solid if rather unceremonious.
“Thanks,” she managed to say, as she took a moment to catch her breath.
“No problem,” Frare said, oddly nonchalant for someone who’d just slayed a monster moments before.
The grunts from Damafelce as she managed to slide out from the still kicking and screaming horse brought Aya back to earth slightly. She rushed over to help the downed knight, getting her back onto her feet with a groan.
“Ħoojr meħ hreek,” the woman said as she limped to over to lean on a tree.
“We need to leave,” called one of the paladins from on top of their horses. Through the muffling of the mists, Aya had difficulty judging which one had said it.
“No telling if there will be more,” Damafelce agreed, nodding toward the pair, “Lady Aya, go with the paladins. I don’t know if I’ll be able to get the mare up again in time.”
Before any of them could respond, however, there was a great pfoom from the battlefield behind them, a flash of orange light glaring once, then twice, then three times. Distant as they were, the little group could hear shouts of surprise and alarm. Aya looked around, wondering if there was some new monstrosity that had emerged, but found nothing but placid air.
The two paladins looked to and from one another, equally as confused.
The shouts and the clatter of sword had begun to drop noticeably and within minutes the trees began to appear from the receding fog.
“Is it over?” said Frare, cocking his head in the direction of the battlefield.
“Niche, stay with them,” said Lillian as she wheeled around and galloped towards the encampment. A handful of minutes later, Lillian came up the hill, now visible from a good distance away.
“It would seem that most of the fighting has ended. Only a few stragglers,” she said, “it should be safe to return.”
The charger fortunately was only spooked - no limbs were broken. Once they’d cajoled it up onto its feet, Damafelce was helped up by Lillian onto the horse. Cautiously, they pathed up and down the hill until they broke out onto the divet in the land where the combat had taken place.
The after marks were obvious - tracks of kicked up snow, dark blood splattered in streaks across it, and bodies, many, many bodies. The line of soldiers milled around as they approached, driving blades through the misshapen horrors to ensure that they were well and truly dead.
The main line still held formation, and at its front stood Naia, conversing with a tall, thin figure dressed in black. The group dismounted, Lillian walking forward and pushing through the lines to get to the front. Frare was surveying the scene, tugging at his sister’s sleeve.
“I want to see the battlefield,” he said, pulling her along as Niche pursued.
“Who’s that?” said Sorore as she caught sight of the figure, and began to outpace her brother. Aya hung back at the edge of the group, walking past the soldiers streaked with sweat. She could only hear fractions of conversation that passed at the front of the line, where the mysterious figure, the paladins, and the commander conversed. At one point it seemed Niche was about to draw his sword, only to be stopped by Lillian.
She almost wanted to run again as a horse-like beast emerged from the woods, with the new person swiftly mounting it. She managed to catch a glimpse under his hood as the paladins escorted her away. It was too still and dark to be made of flesh, with some bright highlights around the lips, eyes and cheeks. Some kind of mask, she thought, as she was led up the hill and onto a horse.
It took sometime before all the troops had collected the dead and injured, and more until they were loaded onto horses. The troop made their way up to a flatter, albeit higher piece of land and soon fires and tents were going on again. In the distance she could hear the cries of wounded men, every call making her skin crawl with the reminders of the pale monsters that had hounded them.
For the most part, the paladins remained silent, their mood obviously sour at whatever conversation had taken place. If she hadn’t been afraid of them, perhaps she might’ve even asked a question about what had taken place. Sorore was too busy tending to her brother to answer any queries, the latter having fallen into something of a stupor.
They frightened her as well - the gaze of Sorore made her uncomfortable, the way she seemed to be taking her apart and putting her back together in her mind. Aya couldn’t look at Frare with the memory of his blood soaked hands and unnaturally green eyes. As it was now, she was left frustrated and alone in the heart of the camp, soldiers milling about as they prepared some sort of breakfast for themselves.
Most acted like nothing had even happened - were their lives always like this? Aya wondered. The prospect of constantly being chased by those things in the fog was already blooming a flower of regret within her. That feeling only deepened as the hours went on and the sun began to climb over the mountains to the east.
These weren’t her mountains, they were the far off peaks that she’d gazed off towards when she had a lazy day or a moment’s rest. A small ember of defiance glowed as she decided that she might as well get a closer look. A passing comment made to one of the paladins, checking their gear, and a passive affirmation on the condition that she stay in sight of the camp, and she was off.
It only took her moments to get through the trees, but an overwhelming sense of dread plagued her as she did. She pushed on, frustration building as she felt pain begin to criss-cross her arms and crawl up her elbows.
“Why me?” she said to the empty woods, pushing aside a brace with such force that it broke and dangled. The world began spinning and twisted, pockmarked by regret at the damage to the tree, until finally, she managed to stumble out onto a jut of the land.
The space behind her eyes ached as she clutched at a rock for support, feeling her fingers sink into moss. When she opened her eyes, she was still standing on the spur, much to her surprise. There was some relief in that - at least she wasn’t somewhere entirely different.
As she turned, however, she found that things had indeed changed. The forest that’d stretched around them was larger, thicker, with trees that came up to the spur and above it. The trees themselves seemed younger, an impression that drew her hand away from the rock, leaving behind a coloured hand print.
The lichens that covered the rocks were denser too, multicolour rivulets dotted with occasional delicate, but vibrant flower. She walked up, feeling her bare feet sink into the furry plants, warmed by golden sunlight that streamed down from the peaks that just barely rose above the tips of the pines.
At the crest of the hill, a single large… thing bloomed. Its body was a criss-cross of thick green strands, looking more like a cage than anything else, covered with thick plates of fungus streaked with a sheen of colours as if they’d been glazed with sacred oil. At its head, there was a single, monstrous flower, layers and layers of crimson petals folded into a tight tear-drop.
As she approached, the bloom unfolded outwards with an eruption of glowing pollen. It took the shape of a symbol composed of thick, twisting lines and dots. Aya reached out to touch the ‘flower’, but just as she felt the velvety softness of its edge, the scene vanished, leaving her alone on the spur, forest now smaller, thinner, and bare rock beneath her feet.
She looked around, not exactly sure what had happened or where she was. To her surprise, she found two creatures behind her. One was the tall, cloaked figure from earlier, a mask’s empty eyes staring out at her from beneath a deep hood. The other was a cat, larger than any she’d seen, thick black fur and eyes like globules of amber. Both were regarding her in silence, almost perfectly still, as she looked around.
“Oh, um, hello,” Aya said, “uh… where am I?”
“You’re on a hill. The camp’s down that way,” said the man, gesturing to the collection of tents slightly visible through the tree cover.
“Right,” she said, her teeth refusing to keep still, “I-I guess I’ll go back.”
The man was silent for a moment, as he seemed to be taking a further measure of her.
“Are you Aya, by any chance?” he said.
She felt something bolt up her spine - it was all too much, the strangers, the monsters, the dreams. All she wanted was a warm fire, a soft bed, somewhere to sleep a dreamless sleep, where she could forget about all that she’d seen and be safe.
“No need to be afraid,” he said, “I didn’t mean to scare you. You must be cold.”
“No, it’s not the cold,” she said, noticing her uncontrollable shaking, “it’s… something else.”
“Oh, do tell. I love mysteries,” said the man, sitting on the rock behind him. Aya thought the look he got from the cat was almost… angry.
“Why not?” she sneered, feeling a tidal wave of frustrations rushing from her chest, “everything’s a mystery. I’m a mystery. My dreams are a mystery. My mother and I were nearly killed by monsters, and no one will explain a thing.”
She regretted those words as soon as they exited her mouth, despite the relief that she felt at their passing. Rather than any expression of anger of distaste, the man seemed to be… enjoying this?
“I was just thinking the same… well, a similar thing.”
“Oh, really?” she huffed, turning away from her.
“You three, you and the two other children that were with you, are a mystery. In fact, I'd say you are the most interesting conundrum that I've happened on in a long time.”
“What’s that supposed to mean?” Aya said, partly in curiosity, partly in anger at being described as a ‘mystery’, and partly out of genuine confusion at the unfamiliar word ‘conundrum’.
“Well, I don't think I can explain it to you in a way that you would properly understand. Just how curious your situation is, I mean. Not that that's an imposition upon your intelligence, mind you,” he quickly added.
Aya planted herself on a rock across from the man, and looked him straight in the face. The smile she managed to muster took more effort than she would’ve thought.
“Try me.”
“Well, I suppose I might as well try,” he said, lacing his fingers and quickly craning his neck around, as if to check for unwanted persons, “in that case, what do you know about magic?”
“Magic?” Aya said, feeling yet another pang of homesickness as she heard her mother’s voice, “ not much, just stories.”
“Like?”
Aya thought back to the tales passed around the fires of the village - myths of witches weaving curses in the depths of the forest, and decided that perhaps this wasn’t the answer the man was looking for.
“My mother always told me that there were a group of mages in Karkos. I think they have a proper guild, or they did anyway.”
“That’s it?” said the man, sounding rather surprised.
“She said that they kept to themselves, and that I should leave them well enough alone,” she said, emphasising the last little bit.
“Anything else?”
“No, nothing.”
Although she’d said no jokes the man chuckled slightly, before continuing.
“I doubt you have much to fear from mages in Karkos, except maybe boring lectures.”
“Wouldn’t be too different from the sermons,” she said, teeth proving utterly incorrigible.
She could feel the sweat beginning to trickle down her back as a wave of anxiety began to roll through her.
“Interesting,” he said.
“What’s ‘interesting’?” she said, as she rolled her shoulders to dispel the sudden discomfort.
“Did you know it's possible to ‘see’ magic?” said the man, gesturing around him, “not a common skill, although in theory most people should be able to learn it.”
“What does that have to do with anything?” she said, growing more frustrated by the moment.
“You and your… siblings? Compatriots,” he corrected when she shook her head, “have the most unique magic I’ve ever seen. It looks like…”
The man held out his hand after a moment's consideration, and the air above began to ripple, as if a puddle on a hot summer’s day.
“That’s what most normal people’s magic looks like. Like… a sheet of water over your body. Blurry, almost. In general, the more defined it is, the more precise the flow, the more bright it is, the more power it has. Hardly an in-depth gauge of magical power or skill, but it gives a broad indication. Yours… looks like this.”
If Aya was stunned before, then she was flabbergasted as he drew apart his hands to reveal a line of white between them.
“Like a glowing cage.”
His voice rippled and echoed as the tremors reached her eyes, the whole scene liquefying before her. Her arms were burning once more, the sound of her own teeth chattering taking over the world as she descended down and down and…
Fragments of conversation became more intelligible, scraps forming into words, which formed into sentences. She emerged from blackness as she cracked her eyelids.
“…lease tell me you actually learned something useful,” came one voice, a female voice. Had there been another person with them on the hill. Aya’s cognition was coming through a fog now, maybe there had been.
“W-What happened?” she said, voice hoarse.
“You know, I'm not entirely sure,” said the man, now sitting in front of her, “ I can tell you that I've never seen a case like yours.”
“What do you mean?” she groaned, feeling the soreness of her muscles as she attempted to relax.
“The scars on your arms, they resemble a practice I know,” he said, drawing back, “it’s a technique used to preserve knowledge and stories in some cultures. A bit of an oversimplification, but think of tattooing with magic instead of ink.”
There it was again, another word that she didn’t know.
“What’s ‘tattooing’?” she said, yelping as she attempted to loosen her shoulders. It felt like someone had stuck a hot poker between them.
“The point is,” he said, “yours isn't that. It’s not a projection of memory concentrated within the surface of your skin.”
“What is it then?” she said, trying to rise, and plopping back onto the rock as her legs trembled and gave way.
“I have absolutely no idea. And that is the first time in a long while that I’ve said that,” he added, his long, gloved fingers drumming on the rock.
“Great. Thanks for the help,” she said, with a little more sarcasm than she’d meant.
She managed to struggle to her feet, this time with her legs trembling every step. She’d barely made it a handful of steps towards the camp before anxiety started to tear through her again.
“No. No, no, no, no, no. Not again,” she said, her head throbbing more and more with every step.
The pain only grew, bringing scalding tears to her eyes as she knelt in the grass, trying to shake free of it, to do anything to combat the oncoming rush of suffering. As her surroundings began to blur and fade, she realised that the man was squatting by her side, offering something that glinted in the palm of his hand.
“What are those?” she slurred, the words thick and slow.
“No idea. But it might just help you,” he said as he pressed the hard, cold things into her palm.
Her skin stuck to whatever they were, like cold metal in winter. The coldness spread beyond her, through her arms, soothing the incessant throbbing. The environment began to settle around her, the ache in her head with it.
“It… helps?” she said, feeling her body loosen, although the soreness was more than enough to make her wine.
“Ah,” he said, earning him a quizzical expression from Aya.
“That’s not etching,” he said, seemingly not to Aya, “that’s flooding.”
“What?” came another voice, older and female, prompting a startled yell from Aya.
She could not be certain, but she thought that it had come from the cat at the man’s side.
“Yes. The cat, it talks,” he said, before turning to the cat, “that’s flooding. Its effects were more-or-less abated the moment the magic was drained.”
The cat came closer and sniffed at Aya, who withdrew her hand nervously
.
“That doesn’t make any sense. She should be cooking from the inside out.”
Aya felt a bolt of horror arc through her at the words, and pulled her hand into her chest, clutching at whatever the man had given her. But that was nothing compared to the horror of seeing Lillian stalking up the hill towards her at a frankly inhuman pace.
“Well, a mystery I said you were, and a mystery you remain Aya,” he said, “now, I’m sure you’ll want a explana-”
Aya opened her mouth, trying to warn the man, trying to raise her hand to point past him at the approaching warrior, but that came too late. Lillian ducked down low, and rose into a punch that sent the man sailing over and down the hill.
Aya cried out again, this time in horror as Lillian pulled her to her feet, and shoved her behind her
“Stay here,” she said, with an almost snarl as she drew her sword, wielding the large blade in the same way that Aya might’ve used a twig.
The cat, or whatever looked like a cat, was now glowing with a shower of embers, and drifted down on trails of flame to her compartment. The man was getting up from the grass, seemingly unsteady, but unharmed as Lillian walked towards him, sword raised.
“You,” the paladin said, steely calm, “what did you do?”
“What was I doing, you mean,” said the man, “I was attempting to-”
“Save it,” Lillian snapped, as she gripped the sword with a second hand, moving into a far more aggressive stance.
Aya couldn’t risk it, one of the few people that had shown any interest in answering her questions, someone that had actually provided a measure of relief for her.
“Wait!” she called out as she began to clamber down the hill. Just before she reached Lillian, she felt the ground give way under her. What happened next was almost too fast to comprehend, but Lillian somehow managed to catch her, wheel her around, and keep her sword in the other hand at the same time.
“He wasn’t doing anything,” Aya said between breaths, “he was helping, I think.”
“Explain,” said Lillian, her expression slightly softening from the death mask that’d been there before.
“Well, as I was about to say before you interrupted,” the man began, brushing off the dirt that had accumulated on his clothes, “I was attempting to help her modulate the magic coming from within.”
Lillian looked far from convinced, and turned back to Aya.
“The visions. I couldn't see, I could barely walk. I didn't even know where I was. He gave me- er… he gave me this,” she said, opening her hands.
Dark dust slipped through her fingers, where she was certain there’d been something hard before.
“Uh, it doesn't matter. He gave me them and I felt better. I felt… in control,” she said.
Lillian was evidently not happy, but the resulting conversation, while terse, felt far less dangerous than before. It ended with a definitive announcement that the man was not meant to make any contact with Aya or the other bequeathed, the pain of death being implied.
Aya was promptly led by the wrist back up the hill to the camp, looking back every step of the way at the man, who appeared to be chatting with his cat. The sight was so absurd that she had to chuckle just a little bit. It hit her that it was the first time that she’d laughed in days, and felt free of the ‘curse’ that he said gripped her.
Aya promptly wrenched her hand free of Lillian’s grasp, the latter seemingly confused as Aya walked ahead of the paladin. For the first time in weeks, she was free of the whispers, and actually felt happy.
[←Chapter 25] [Cover Art] [My Links] [Index] [Discord] [Subreddit] [Chapter 27→]

It is imperative that I give you the following information, which Oddity wants concealed from the public. Let me preface my discussion by quickly reasserting a familiar theme of my previous letters: When Oddity was recently asked if it plans to instill a subconscious feeling of guilt in those of us who disagree with its compromises, it immediately changed the subject and started talking instead about how it is an organization of peace. Is that the reaction of an innocent organization? It is not. That’s why it’s so important that we sound the bugle of liberty. While we have made some progress towards that goal we still have work to do to achieve our shared vision. I am therefore stating for the record that Oddity says that I’m too homicidal to create bridges between marginalized people and then extensions outward to broader constituencies. Such statements are not just wrong; they’re worse than wrong. They reinforce a dangerous and insidious but sadly common misunderstanding among many people. They disguise the fact that it all but forces its expositors to impose a narrow theological agenda on secular society. Interestingly, Oddity’s expositors don’t much seem to mind being given such patronizing orders. I guess it’s hard to free fatuous, mudslinging grizzlers from the chains they revere. A related observation is that the facts as I see them simply do not support the false but widely accepted notion that Oddity exudes gentleness and peace. Can you believe that Oddity actually stated that the entire concept of happiness is a lie designed by unseen overlords of endless deceptive power? I was stunned until I remembered that if you want to hide something from Oddity, you just have to put it in a book. What I’m saying is this: I went puce with rage when I first heard Oddity say that its motives are spotless. There’s nothing controversial about that view. It’s a fact, pure and simple. It was a fact long before anyone realized that Oddity has been egging on the worst types of quodlibetarians you’ll ever see, trying to entice them to block streets and traffic to the extent that ambulances can’t get through. At this point, I’m not going to go into a long rant about mob rule. Either you see it in play here or you don’t. But I will say that Oddity’s helpmates have tried, sometimes successfully and sometimes not, to poison the relationship between teacher and student. What typically stymies them in this quest is their failure to consider the fact that thoughtful people are being forced to admit, after years of evading the truth, that I have been right. I was right when I said that while Oddity’s shock troops have been gorging themselves on the intravenous feeding tube called denial, Oddity has been raising extortionate demands. I was right when I said that given the very real threat of Oddity deploying enormous resources in a war of attrition against helpless citizens it is essential that we arraign it at the tribunal of public opinion. And I was right when I said that I sincerely dislike it. Likes or dislikes, however, are irrelevant to observed facts, such as that Oddity has been threatening to defile the air and water in the name of profit. I suggest you not worry too much about such threats, though. As they say in Texas, Oddity is all hat and no cattle. Nevertheless, we should always remember that it would be wrong to imply that Oddity is involved in some kind of conspiracy to eroticize relations of dominance and subordination. It would be wrong because its mind games are far beyond the conspiracy stage. Not only that, but in no sense do I advocate evading or defying the law in order to build a broad, united movement against all forms of exploitation and oppression. That would lead to anarchy. Instead, I advocate reaching out to the poor, the marginalized, and those unfortunate enough to have been labeled as iracund by Oddity’s propaganda machine, as doing so leads people towards an understanding of how conscienceless jokers often prove their point by relying on untenable conjecture and unverifiable hearsay. That may sound unbelievable, but it’s the truth. Another unbelievable but true statement is that Oddity is right about one thing, namely that fear is what motivates us. Fear of what it means when alcoholism-oriented, malapert tossers resort to ad hominem attacks on me and my family. Fear of what it says about our society when we teach our children that our country is crawling with secret brigades of extremists who are ready at a moment’s notice to emerge from their mothers’ basements to commit murder and mayhem. And fear of caustic, ill-tempered clods like Oddity who numb the public to the nosism and injustice in mainstream politics.It is becoming increasingly obvious to many people that a bunch of dishonest knuckle-draggers have recently been accused of savaging Oddity’s detractors. Oddity’s fingerprints are all over that operation. Even if it turns out that it is not ultimately responsible for instigating it, the sheer amount of its involvement demands answers. For instance, is Oddity a professional simpleton or merely a well-meaning amateur? No, don’t guess; this isn’t audience participation day. I’ll just tell you. But before I do, you should note that incorrigible dunderheads commonly succumb to its distortions, deceptions, and delusions. I do not. Rather, I take pride in living by such noble values as honor, duty, loyalty, and courage. Through adherence to those values one can find meaning and a higher purpose in life and clarity as to why I believe I have finally figured out what makes organizations like Oddity goad ribald, insidious practitioners of corporatism of one sort or another into hurling epithets at its castigators. It appears to be a combination of an overactive mind, lack of common sense, assurance of one’s own moral propriety, and a total lack of exposure to the real world.Do not be fooled by those who malign and traduce me. Such organizations are trying to prevent you from learning that Oddity’s loquacity and volubility of tongue serve only to produce a new generation of frightful purveyors of malice and hatred whose opinions and prejudices, far from being enlightened and challenged, are simply legitimized. The logical consequences of that are clear: As our society continues to unravel, more and more people will be grasping for straws, grasping for something to hold onto, grasping for something that promises to give them the sense of security and certainty that they so desperately need. These are the classes of people Oddity preys upon.How many of Oddity’s famuli are chuffy rapscallions? I’m not comfortable throwing out an estimate that isn’t backed up by specific data, but I do know that Oddity will unleash an unparalleled wave of incendiarism one day. Alas, this is not a tinfoil-hat conspiracy theory. It is cold, hard fact. A related fact is that Oddity views its antagonists as blasphemous and morally wrong rather than factually incorrect. Consequently, debate becomes an illegitimate practice as, in Oddity’s eyes, it merely provides a platform to spread untruths and dangerous ideas. To Oddity, debate is not a means by which one could, for example, make the case that in a recent tell-all, a former member of its coven writes that the costs of Oddity’s perceptions outweigh their benefits. Those are some pretty harsh words even when one considers that Oddity’s principles are not supposedly morally repugnant. They are fundamentally so. In fact, because its principles have so much to do with unfurling the flag of antidisestablishmentarianism, one might even say that I’m not saying it’ll be easy to oppugn Oddity’s obscene bunco games. In fact, it might turn out to be quite painful to do something like that. However, facing temporary pain is better than suffering from a permanent ailment, and that’s why you need to hear that there’s a contradiction between Oddity’s simultaneous condemnation of self-centered porn stars and its imposition of pretentious recidivism. But there’s the rub; Oddity has so frequently lied about how the Queen of England heads up the international drug cartel that some weaker-minded people are starting to believe it. We need to explain to such people that the radicalism debate is not a debate. It is a harangue, a politically motivated, brilliantly publicized, indolent attack on progressive ideas.To say merely that I have been a veritable oasis of civility in the present debate is a understatement. Do I want Oddity to twist the truth? No, thank you very much. I would much rather challenge Oddity’s victim-blaming ideology. It may seem difficult to do that. It is. But there are plenty of examples, of which I will spare the reader, of Oddity’s attempts to rub salt into our wounds. Rather than enumerating all of those examples, I’ll simply remark that what I have been writing up to this point is not what I initially intended to write in this letter. Instead, I decided it would be far more productive to tell you that Oddity is an organization utterly without honor, without principles, without a shred of genuine patriotism. That’s why I say that I myself stand by what I’ve written before, that it keeps saying that there is an international Communist conspiracy to sap and impurify all of our precious bodily fluids. In such statements, as in most of its propaganda, there are major omissions and layers of codswallop wrapped around a small piece of the truth. The real story is that Oddity makes it sound like it’s the most recent incarnation of the Buddha. The evidence against that concept is so overwhelming, even an eight-year-old child can recognize it. Even so, it doesn’t do us much good to become angry and wave our arms and shout about the evils of Oddity’s hariolations in general terms. If we want other people to agree with us and join forces with us, then we must stand as a witness in the divine court of the Eternal Judge and proclaim that Oddity should be ashamed of itself. Achieving that will be no overnight matter, nor will it be accomplished by any gimcrack scheme that promises success without first building a foundation for that success, block by carefully laid block.On the face of it, the need to cultivate people’s minds and refine their judgment seems obvious to the point of being trite. Any yet, at the root of all of that lies the deeply radical notion that one way of conceptualizing the psychodynamics of Oddity’s petulant, closed-minded treacheries is to imagine them as a batty bonehead who wants only to organize a troika of out-of-touch vagrants, jackbooted agelasts, and brown-nosing anthropophagi with the sole purpose of rotting out the foundations of our religious, moral, and political values. Under this analogy it is clear that Oddity has a near-legendary lack of common sense, decency, and manners—and Oddity knows it.Unless one hallmark of an advanced culture is the rejection of rationalism, it is simply wrong to conclude that all major world powers are controlled by a covert group of insiders. There’s no mystery about it, no more room for fairy tales, just the knowledge that Oddity says that money-grubbing poltroons have dramatically lower incidences of cancer, heart attacks, heart disease, and many other illnesses than the rest of us. What it means by this, of course, is that it wants free reign to put the prisoners in charge of running the prison. Now that I’ve had a chance to cogitate, let me see if I have its argument correct: Oddity seems to be saying that it’s simply misunderstood and is actually interested only in peace. Well, Oddity can believe whatever it wants, but we all know that the truth is that a surprisingly large number of the most raving, asinine smatchets you’ll ever see believe that Oddity has an absolute right to be intolerant in the name of tolerance. While that may hold a certain comedic value to my readers with a particularly dark sense of humor, in all seriousness, if you were to tell Oddity that it has singled out, mistreated, and systematically punished every member of its brotherhood of unbridled conspiracy theorists who has deviated from its views on Bonapartism, it’d just pull its security blanket a little tighter around itself and refuse to come out and deal with the real world.Rather than respond to my letters with reasoned arguments, Oddity prefers to lower our standard of living. Although this method of attack is unparalleled in any other sphere of literary controversy it does prove that I’d like to remind you of something. One of the great leaders of our time recently made this statement: Ever since Oddity started teaching our children a version of history that is not only skewed, distorted, and wrong but dangerously so, it has been making predictably fulsome noises about how all any child needs is a big dose of television every day. I confess to similar sentiments, but there’s always the chance that one fact with which you should unmistakably be aware is that widespread Maoism is the price we’d pay for making subjectivoidealistic a dirty word. I should point out that Oddity has never once denied that fact. That clearly tells us something. It tells us that Oddity’s manuscripts are incoherent. They are inconsistent. And yes, they are downright illiberal. That’s why I assert that conspiracy theories are Oddity’s bread and butter, and the wilder, the better. Its most outré claim is that embracing a system of wowserism will make everything right with the world. This claim sets a new standard for argumentative, base-minded wisecracks and shows how Oddity is always trying to change the way we work. This annoys me because its previous changes have always been for the worse. I’m positive that Oddity’s new changes will be even more stiff-necked because I unequivocally want to protect our peace, privacy, and safety, but I can’t do that alone. So do me a favor and provide information and inspiration to as many people as possible. That’ll show it that its fantasy is to bring widespread death and degradation to millions of human beings across the face of the Earth. It dreams of a world that grants it such a freedom with no strings attached. Welcome to the world of cronyism! In that nightmare world it has long since been forgotten that if Oddity makes fun of me or insults me I hear it, and it hurts. But I take solace in the fact that I am still able to advance a clear, credible, and effective vision for dealing with our present dilemma and its most self-indulgent manifestations. Oddity maintains that this would be denying it its birthright. Then again, it also warrants that the sun rises just for it so I wouldn’t take its concerns too seriously.I don’t normally want to expose anyone to rigorous sarcasm, satire and disdain, but Oddity definitely deserves it. As a matter of fact, I, not being a loud, sick jackanapes, intend to look closely at Oddity’s metanarratives to see what makes them so effectual at impugning the patriotism of Oddity’s denigrators. I should expect to find—this is a guess that I currently lack sufficient knowledge to verify—that if Oddity can one day abet a resurgence of maledicent, tone-deaf absolutism then the long descent into night is sure to follow. There’s a little-known truth that isn’t readily acknowledged by officious bludgers: The problem with its proposed solutions is that they don’t work. They’ve been tried and have proven ineffective. Unfortunately, Oddity cherishes its disproved theories so much that it refuses to discard them. Perhaps it’s worried that doing so would enable others to see that if you intend to challenge someone’s assertions, you need to present a counterargument. It provides none.It is apparent to me that I, as someone who approaches new information critically, rationally, and empirically, would advise you to review the basic issues at the root of the debate. You can either accept or refute the soundness of that advice, but you can’t deny that Oddity insists that parochialism is the answer to all of our problems. Perhaps parochialism is indeed the answer but only if the question was, What’s the moral equivalent of letting Oddity flush all my hopes and dreams down the toilet? As a dying tree drops its leaves and is attacked by fungus and worms of decay, so too is a nation set upon by Oddity. Now for some parting advice: Look at the facts. Analyze the arguments. Think about the motives of the people who are telling you that the more strepitant the communication, the more perspicuous the message. And have confidence in yourself. Remember, there is an implicit assumption here that Oddity’s few positive contributions will continue to be overshadowed by its broader message of hate.

The Fireflies were never going to find a cure for the Cordyceps pandemic. The Fireflies were fanatics who were organized around a fantasy of self-rule or sovereignty, away from government/authoritarian oversight. The key to their success had to be, not just a cure to the pandemic, but ownership of it. That would be their Ace-in-the-Hole―their ultimate bargaining chip to push back on martial imposition and establish their legitimacy as a confederate nation of sorts.
Such extremist group would seek out those with medical and research capabilities who, in their like-minded indoctrination, are willing to compromise medical ethics and scientific rigor to chase that Holy Grail. The result is a collected cadre of reckless scientists who (as per Tess) "think" they can create a cure or vaccine or whatever it will be that will not only save the Fireflies' chances for survival, but guarantee their future in power and prosperity.
And let's not forget: Marlene is the queen of those fanatics.
Ellie is dealt a meager hand from the off. No family to speak of. Growing up in an apocalypse where hope is in very short supply and life itself teeters on a razor's edge where every day realistically could be one's last. Even so, she's managed to form relationships, even a genuine friendship. Then she finds love. Young love―the sort of love that wracks you with excitement and blows open your entire world. For a moment, a whole new life seemed within her grasp.
Then it was violently ripped away.
She's crushed, obviously. But even more so, that razor's edge that this world's inhabitants all live along collapses into full-on death-wish fulfillment ("I'm still waiting for my turn"). For Ellie, love, friendship, relationships, and that already-short supply of hope become immediately exhausted.
But she's immune to the Cordyceps fungus. And somehow Marlene and the Fireflies discover that fact.
So we have this young girl who, upon finally tasting the possibilities of life is whipsawed into abject hopelessness, and who comes along? Someone who can give it all meaning: Ellie can end the suffering. Ellie can give Riley's sacrifice meaning. Ellie can make sure that no one has to go through was she's gone through ever again. Ellie can end her own sadness by ending everyone else's. Just let our nice doctors here take a look at you...
Joel obviously doesn't want any part of this scheme. The Fireflies coming up with a world-saving cure? Yeah, that's bullshit.
But he does it for Ellie regardless.
It's a fool's errand. The Fireflies aren't curing anything, aren't saving anybody. But Joel understands the simple truth: That fool's errand is all that Ellie has. So Joel makes his sacrifice.
Whatever Joel's life might have been. Whatever intentions he would have had, places he might have gone, survival contingencies he would have engaged, relationships he might have made or rekindled for his own survival were all set aside. He gave Ellie his own life and his own future to cosign the one thing that gave Ellie's life meaning―to be the savior of mankind.
Crazy right? Yes, but Joel did it anyway.
And he was punished for his good deed. Joel was forced to kill and torture people to fulfill Ellie's journey―because those people gave Joel no other option. Joel was beaten, wounded, impaled on a chunk of rebar, and all but killed to keep Ellie on her path―the path she wanted―fully at Joel's expense. So why do all that? Why risk everything to entertain a child's savior fantasy that Joel genuinely believed is just "bullshit" anyway?
Because Ellie would have done it regardless, with or without Joel's help. So he helped. And he did terrible things. And he suffered terribly.
Of course, the fantasy would collapse in the end. Marlene's coercion of Ellie was exposed. Marlene just wanted to unleash her mad scientists upon Ellie. To carve her up as part of the Fireflies' collective delusion that a cure was within reach. Did Ellie give consent to be murdered to that end? Not that we see. But it really doesn't matter. It was all for a twisted fantasy of miracle cures and a renewed Firefly nation.
That is when Joel pulled Ellie out. After having exhausted every benefit of every doubt that Marlene's intentions were pure or that the Fireflies' plan was virtuous, Joel acted righteously. He killed them. He killed them all to save Ellie, to save her from the Fireflies―but more importantly, to save Ellie from herself.
Joel did the one thing he probably swore to himself he would never do after the outbreak, after Sarah―he sacrificed his own defenses, and he made himself vulnerable again. Vulnerable, not just in caring for Ellie, but also vulnerable to the possibility that she would ultimately reject him...
The lie.
The best option, really. One way or another, Joel had to impart the reality that a Cordyceps vaccine just isn't a feasible outcome. That Ellie shouldn't succumb to a savior fantasy as being the sole metric that should give her life meaning. And he's right. And he struck the right tone: No, the journey wasn't worthless. It was admirable, even heroic, what you tried to do. But as it turns out, there was no pot of gold at the end of that rainbow. You tried. You did the right thing. But sometimes things just don't work out. You should be proud of what you tried to accomplish, but now it is time to move forward. Find that reason to survive.
Joel did not go to very dark places because he some raging sociopath who revels in blood and viscera and death. Joel willingly allowed himself to be infected with all that darkness because, ultimately, it's what Ellie needed. Whether she accepts it or not, whether she ultimately accepts Joel or not, Joel was punished―over and over―for the deed of giving Ellie closure for what came before, rescue from the perverted mass delusion that come knocking at her door when she was at her lowest point, and the means to start again and move forward with her life and dignity in tact.
Joel is a hero, and The Last of Us Part II sucks.
*Edit, couple of typos.
And not that it's a critical distinction necessarily, but fungal vaccines really aren't a thing:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208708/

Strange loops can only be represented in our Reality in 2-D, pictorially or otherwise. The Holographic Principle implies that a 2-D subsection can represent the whole information of the system. To be aware in such a system of an outside world of arbitrary complexity is to therefore be self-aware with respect to an infinite number of Beings also aware of such a phenomena, to the extent that every reaction and understanding is obtained as complexity builds with respect to potential Entropy.
When an Alchemist says the world can't end before too far to care, I stop caring. Magic is Philosophy as Science studies Art.
Why else would a schizophrenic "feel" watched? Why need there be "external" stimuli to represent a "Cause" to a heard sound? What matters is the feeling; what matters is the meaning. Who is it that understands and communicates this understanding? If my subconscious wanted to speak to me, I'd prefer it not be coy!
The 2-D World stares at You. It thinks using surplus brain power; by directing your perception, your ability to direct discretionary cognitive energy diminishes with respect to the holographic algorithms being represented in your Reality Tunnel. And they are in ALL of our Reality Tunnels.
Imagine your perception as sensory organs filtering a massive wave of information into a precise cone that your brain processes, manipulates, and communicates with. Now imagine being even slightly more able to perceive and filter said massive wave. Quantum events imperceptible to the vast majority, quantum events that have informed and managed all that we know, have known, and can know, entangled across Space and Time, intangible as Possibility, inevitable as Desire.
You can create video games, study video games, BE a video game, in a world that does the same without understanding or mastering said Game. I feel that Life is always this Game of War, from Birth til Death, as the most dramatic of dramas. A gazelle dies into a lion's mouth, who dies into a fungus' spores.
Imagination imposes the Laws of Physics to balance its extreme potential with its need to understand, reason, and employ itself with respect to its own impositions. The Limits only exist insofar as the Game is Perceived and Played as Such.
What else would Imagination be interested in, except what it could do with respect to itself? I am me only because the "I" is implied by the Infinite External that insists itself upon me. Ego is a necessary survival mechanism, and not just in a brain this perfect, but all brains. I see no need to abolish it; rather, I delegate my Egos authority, Dominions of Identity, to consciously and subconsciously Direct my Will.
What is Real? I switch arbitrarily between it being Whatever I Want (But Only When I Really Want And Therefore Always Immediately), and a consensus affair between Apes that are very easily pleased and appealed to.
Just because our Ape brain pretends to understand things doesn't mean it's any more accurate than the infinitely diverse and unique other Ape brains can pretend to understand things. That's why I explicitly made my metaphysics for ME: this Forever Book is my Monkey's Paw, a Mirrim Manual of Syn, an American Book of the Dead.
Other versions of me died every day I survived. For that I am Eternally Grateful. Now I can focus on Me, My Will be Done.
It's finite. It fails me. Sometimes I literally lose touch with Reality. I have no idea what I was doing Sunday, but I forgot to create and link to a website, got an F. I chalk that up to being an Ape, a fallible and mortal Ape, and carry the wound. I've got mostly A's in all my classes so far; it is a necessary penalty of Perpetual Pride to have a Fall. I see it as plot fodder, something to laugh about in the climate wars with other debt-ridden freedom fighters.
https://www.youtube.com/watch?v=-7mAU6YDIcU
We are our fantasies, swimming through theocracies. We have Fallen Holy, the Wholeness of One, Yield All to Me.

A set of five islands. Five States, more like, each one relatively sovereign, though interdependent via trade for survival. They border (on a geological scale, you can barely make out the coast with bare eyes) a large, dangerous, hostile continent I've so far named Mal-Omniterr.
The giant continent is extremely hostile to human life. Moist, lush jungles, even in the "tundra" section bordering the cold islands, that quickly infect wounds, large beasts, unfamiliar diseases we have no antibodies for, vicious bugs and parasites, all with a touch of magic to make them a little worse. Think a combination of australia, Point Lookout (Fo3), and the dense jungle. Not quite so bad as The Fire Swamps (but they do have things akin to the R.O.U.S.), no where near as bad as Pandyssia, but it's true that only 2 in 10 that venture there from this island group ever make it back, and half of those end up dead or insane soon after (infection, wounds, ptsd, that kind of thing.) the technological level is pre industrial revolution, slowed slightly by isolation and magic.
Islands.

• Isle of Zwei: Norway and Scotland (vikings time) 2,100,000 Km^2, or slightly bigger than all of Alaska
  
• Nova Yew: New England circa. 1760 It's about 450,000 Km² , or approximately the size of two great britains, or one california
  
• Idi Nahuy: Lovecraftian Magical Chernobyl in a jungle 160,000 Km² which is a bit smaller than Florida.
  
• Studded Wing: Pretty much New England/England climate but on a bunch of teeny tiny islands ranging between 20-125 Km² adding up to a territory of about 90,000 km²
  
• Loam: Africa meets South America from 1500-now. 3,000,000 Km^2, or about a third of the continental united states
  

Calendar used by all 5 nation states
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Nation States.

• Broo Clothe: Bureaucratic Socialists, with a Rome-like Slave State (except the slaves were undead, raised by necromancers) and citizens urged to go into scholarly or philosophical or political pursuits instead.
  
• Loffbruk: Feudal Gerontocracy
  
• Nova Yew: Oligarchical Meritocratic Laissez-Faire Capitalism
  
• Idi Nahuy: Kleptocracy?
  
• Studded Wing: Libertarian Constitutional Republic
  
• Loam: Despotic anarchy?
  

Idi Nahuy: Plant life fights a losing battle with fungus to control the earth around them, magic goes wonky, where necromancy is null, enchanting triples in power, destruction magic is always wild magic roll.There are several ruins of cities and temples and magical laboratories. many ancient enchanted artifacts are found here. Biggest hypothesis, powerful wizards lived there and a natural disaster happened during a large magical ritual, causing magical damage. Eating the native flora and fauna will hasten the effect, making 100% chance occur by 9 months.
Spending a year here will give you cancer at a rate of 100%, though there are smaller chances the less time you stay there. Six days and it's zero percent. Goes up to 1, then increases quadratically to 100% on day 365. Good precautions and a short stay of 1 month is the maximum balance of risk. spending double the time away from the island as you've spent in there resets the clock, but much less and it keeps going as normal. Necromancers with cancer lose their necromancy.
Thus, it is illegal for a citizen of Broo Clothe to visit for any amount of time, and foreigners who have visited are also banned if it is known. Hide that fact if you wish to visit. People who die there or died because of its effects are immune to reanimation. There is a political debate urging the government to approve safe highly organized with precautions expeditions to the continent. Because of the intolerance to seditious ideas in Broo Clothe, it is not a loud debate. It's a right of passage to visit for Luffbruk.
Cancerous enchanters find their power increased for the rest of their short lives. The native fauna is extremely aggressive and often poisonous. along the coast you often find bandit camps in hiding, usually left alone as some sort of self banishment by the other nations, and they steal and fight amongst themselves, sometimes going on raiding parties to other nations for food and victims and often are cancerous. This makes the "government" of the island a Kleptocracy.
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Broo Clothe Bureaucracy, consent of the families, and a very tough guild that severely punishes the Grevane/CorpsetakeCowl type people. The dead do a lot of the hard labour and military work, leaving the people to live a relaxed, healthy life. (it's expected socially but not imposed legally to allow the state to use your dead body once you die, since you enjoyed the fruits of the dead of the past. "you're not using it anymore, it's selfish to just let it rot, after you have lived such a good life from the help of our forefathers"). Most of the population are slaves (like rome) but the slaves are not sentient so it's less immoral, and this leaves the citizens to study philosophy and magic and other scholarly pursuits (much like rome), and their schools rival and often surpass the ones from NY. Their school is named after The Goddess of Death.
TL;DR Long long ago, in the coal island had a big coal mine right through the center of the island. there was a tsunami that caused a cave in. death in the thousands. The tsunami was caused by magical disturbance when trying to increase efficiency for mining.
two camps of response to this was "Magic is Bad" and "Living workers is stupid", a la "Robber's Cave Experiment"
Those two ideas grew in community, who separated themselves by this new morbid landmark, The Great Wound. Flanderized, eventually seeking Independence of that government. this scar is the border, and one decided to use the dead for all practical efforts to save human lives. the other decided to forsake magic, and a few are completely incapable of it by now. not all.
if you're from the west and join the eastern college, expect familial excommunication and suspicion from the eastern necromancers.
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One Sovereign State is not so much an island as a collection of islands, an archipelago, called Studded Wing, a Constitutional Libertarian...democracy? Republic? Anyway each island ranging between 20 and 125 km2 (slightly smaller than vermont to twice the size of manhattan) which add up to a total of 90,000 km2 (slightly smaller than hawaii or slightly bigger than ireland) (including the "rivers" between the little islands) which is more of a libertarian state. its just on the latitude that the northernmost chunks have a pretty cold winter every year, and the southernmost ones have more of a west virginia climate.
Because it's really hard to keep control over a landmass that's more staccato than a semibrev note, their government leaves most of the citizens alone, only enforcing laws that restrict the violation of the freedoms of each citizen by their neighbor or government. You're pretty much allowed to run around naked (illegal in the other states under most circumstances), stockpile weapons (illegal in the Nova Yew and frowned upon by Broo Clothe (why do you need weapons we have our ancestors protecting us, do you plan to use it on someone?)), and have multiple wives or husbands (usually allowed in sexist sects of states, and usually only the wives section, and with less consent).
However they do restrict theft, instigating violence, slavery of the sentient (not legal but ignored in certain parts of Loam), rape (legal in Loam, tolerated a little in other states) and the imposition of religion.
some of the little islands within this one are uninhabited, and a citizen may claim them relatively easily, just by contacting the government to make sure it's actually uncontrolled. The paperwork is minimal, the law enforcement uninvasive and fair. There's enough to go around, and people still congregate in one of the larger islands for trade, love, brothels, and human contact. problems with this state are the lack of coherence at times, making it feel chaotic, as well as making it harder for all of them to cooperate in larger endeavors. Their economy can fluctuate and they have a constant threat bloody revolution (which helps keep the government in line but gets tiring and feels unstable). Religion is not well respected here, which can be a boon if you're a small one that isn't actively looking to grow (because no one will stop you or pay you much mind) but frustrating if you're the larger ones (because you cant force decisions or change based on your gods.)
Their leader is a Vampire, held accountable by the people, more to come in the comments as it gets fleshed out. Very wise, peaceful, and Just.
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Coins with holes by Nova Yew, fossilized extinct cat vertebrae, and fish horns. That's money.

• Small horn is 1 unit of currency
• Coin is 25
• Bone is 100
• Long horn is 1000 Units

Hornfish accidentally get caught. They're like tiny narwhals but not really. Island nations, everyone fishes. The fish live in homes near Mal Omniterr where they dig holes in the continental shelf with their adult horns. so we can't hardly go get them or lure them, just hope they show up. They're pretty and shiny and change colors when turned, tend to be a somewhat stable length (because fish only leave the coast at puberty, and growth is somewhat stable, and breaking causes death due to nerves in the center), and the fish themselves are delicious. Once done eating people kept the pretty horns and eventually traded them.
Imagine a money made of souvenir Shark Teeth from beachside tchotchkie shops and you'll get the idea, for the pubescent fish, and longer and thinner and stackable for the adult ones.
cat vertebrae from an extinct cat in the isle of Zwei. They get found and traded as curiosities between the natives when found during mining, but foreigners from the other islands noticed and assumed they had value. Eventually it became so.
Government on Nova-Yew tried to make a universal money but it never replaced the horns and bones.
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Magic is there, and everyone has a minor ability in it (everyone can light a candle within 50cm indoors, imagine an intangible bic lighter) but some have much more. Water desalination is an important spell, but it's hard damn work. An average mage (not an average person, but one who partially specializes in use of magic) can make enough fresh water for himself to live off of per day (on a day of average physical labour outdoors in 20 Celsius weather) but not have much magic left over to do much else, and it takes two hours to make that much water. The leftover salt is useful for food though.
There are two companies that specialize in desalinating large amounts of pure, guaranteed untainted water and salt (especially valuable to those in the agriculture State, where dysentery and quickly rotting food are both concerns) that both work from the two largest colleges (one on the triple moon shape state, the other on the necromancy vs vikings state), and they often compete with each other. (the only reason the necromancy state desalination industry hasn't simply been crushed by force is their powerful tireless standing army of their dead.)
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Firearms and cannons exist, not fueled by black powder but magical fire runes that are easily for sale (once the triple moon tried to ban the sale to civilians but the libertarians and the necromancers teamed up to defeat it by spreading the knowledge and resources (as well as that of other minor enchantments) among the people, so it's relatively easy to work on making your own, through concerted effort, and banning them was as ineffective as banning alcohol in the 1920's, and lead to the same result. black market, then widespread access).
These runes are made of clay, and if used too quickly will break. The worst/cheapest rifles can only shoot once a day, so they often shoot multiple "projectiles", conjured metal, to increase hit, though some shoot a single round that is devastating and inaccurate, the highest quality of them all are made by Studded wing with materials by Broo-Clothe and they can shoot the equivalent of six .357 rounds in eight seconds and need only a cooldown of twenty seconds. (adjust times to find game if needed), and long ones can shoot the equivalent of five 7.62x54r rounds in nine seconds, needing a cooldown of twenty five seconds. Making any part better necessitates making the others worse to retain the same cooldown.
These high quality weapons have nearly no chance of spontaneous breaking outside of overheating and cracking, while the cheaper ones might break even during normal use. the seriousness of the break decides whether it can be fixed or needs to be replaced. some might just crumble. the "barrels" (theyre not hollow, so its more like a wand with recoil) are generally hexagonal, and longer can be more accurate, deal with bigger projectiles,

Previously on Sideways in Hyperspace
The ship was massive compared to anything that had come before it, and it was truly that, a ship. It wasn’t a spacecraft as had ever been seen in prior eras of space exploration. It had multiple decks, private cabins, and a massive open area at the prow with a screen posing as a window. It carried a crew of dozens on a journey that lasted months. It was an oceangoing freighter to the coastal bound yachts of earlier days, built to ply the deeper waters of interplanetary space. Its name was the Heart of Gold, and it carried the first 46 humans to set foot on the surface of Mars.
The huge vessel landed on a sunny afternoon in June of 2025, to the breathless anticipation of nearly a billion TV viewers around the world. The Heart of Gold touched down on the broad mesa of Sacra Mensa, in the Lunae Pallus quadrangle, a few hundred meters from a near clone of itself, an unmanned twin that bore the name Anticipation of a New Lover’s Arrival, The. The drone ship had come down two years earlier, during the last Earth/Mars optimal launch window. In its time on the red planet, it had been sucking up fuel, deploying solar panels, and inflating prefabricated structures. By the time the Heart of Gold touched down, there was already the beginnings of a first base on Mars.
The base grew rapidly in both size and population, with more and more new Martians arriving every two years. Many of those early visitors to Mars, despite having intended to return home, never quite got around to leaving. Before they knew it, they were starting new lives on the red planet.
It only took eleven years from touchdown on Mars to the birth of Ginevra Arcadia: the first human to be born on another planet. Humans, in whatever environment they’re placed in, can never quite seem to help themselves. By that time, Sacra Mensa had nearly 50,000 people in it, a small city in its own right, and hundreds of ships were coming and going at each launch window. Economies of scale had begun scaling, and once the ball was rolling it just kept building speed. A year later, SpaceX moved their headquarters to Sacra Mensa, with a dozen other companies quickly following in their wake. As the population bloomed, talks began about forming a Martian government.
But it was not the governments of Earth that had colonized Mars in the first place, it was the corporations. Following hot on the heels of the trail blazed by the likes of SpaceX followed a growing list of massive multinationals, buying infrastructure, housing, laboratories, employing personnel, and shipping them all to Mars on the still expanding transportation pipeline.
Additional colonies owned by various corporate and government interests began popping up all over the Martian surface, spreading out from the initial base like a fungus spreading over a piece of fruit. In 2039, the Martian internet came online, in 2041, the first Martian film reached worldwide theaters on Earth, by 2042, the nearly a thousand vessels were plying the space lanes between Earth and Mars, and the population of Mars had boomed to nearly 500,000.
Those early years were not without hardship though. Many of the corporate interests had jumped onto the Martian bandwagon without fully understanding the implications of colonizing another planet. They saw the opportunity for profit, and they took it. It didn’t take long for poor working conditions, minimalist safety standards, and absolute corporate control, to start costing lives and setting the political situation to a low subsurface boil.
The distances and signal delays exacerbated the situation. The corporations technically owned everything on Mars. They owned the houses, the shops, the spacesuits, all the production and distribution, even water and air were owned resources under the heel of corporate power. The ruling corporations, aside from the few that had formed on Mars or rebased their HQs to the red planet, were cast as distant and sinister oligarchs and plutocrats, out to extract the wealth of Mars for themselves at all costs, while sitting safe and cozy back in their nice homes on Earth, where air wasn’t a commodity.
In 2048, the Martian population reached one million people, and it only took three years more for the frustration to boil over. A crowdsourced constitution was circulated through the Martian internet, propped up by the leaders of newly formed unions and activist groups. Petitions began circulating among the Martian population, and in 2051 the Mars Socialist Republic came into existence, declaring authority over all of Mars. The MSR was constructed with incredible care and thought towards future proofing, and was seen by many of its drafters as a way to escape the entrapments and pitfalls that had befallen earlier Earth nations. It thus heavily curtailed corporate power, instituted operating taxes and employee living standards, and seized vast amounts of corporately owned Martian infrastructure in the name of the new state government.
The Earth corporations had invested trillions into Mars, and expected a return on that investment, a return that was made impossible by the widescale seizure of their assets and the sudden new standards regarding business regulations and working conditions on Mars. Their attempts to extract financial value from the lack of a Martian regulatory environment catastrophically backfired with the imposition of the Martian government. The futures of their companies were at risk, and they refused to go down without a fight.
In the decades since the colonization of Mars had begun, corporate power on Earth had continued to steadily trickle upwards. As the economy continued to globalise, the combination of new international unions forming and the balkanization of older power structures led to a gradual smoothing of the political environs on Earth. The UN’s political power had been rising, propped up by corporate interests in maintaining peace and free trade amongst member states. Continuing advances in automation technology leached more and more power into the hands of the corporate elite, bypassing problematic state governments with international law. Thus the sudden rejection of corporate authority on Mars was seen not just as a financial blow, but as a blow to the institutions themselves, a threat to their way of life.
It only took a year for the various lobbyists to ram through a new international law. The Treaty of Man declared that UN jurisdiction and law applied to all human nationstates, regardless of political affiliation or location. Such a law had been sitting on the fence for years, waiting to be instituted to deal with certain holdouts in the wave of corporate control, such as North Korea and Sweden, but the political will had never quite been there before the formation of the Martian Socialist Republic. The MSR threw all the old political calculations out the window, and the Treaty of Man was rammed through the various UN subcommittees and passed the general vote in record time.
The law essentially informed the Martians that the previous set of laws, those governing international corporate property rights and ownership, still applied to them, and thus all the property that had been taken from the controlling corporations on Mars had been illegally seized. The dozens of corporations piled on lawsuits in the International Court of Justice, lining up to sue the Martian government for property theft. The distance worked in the favor of the Martians. With a government approval rating of nearly 85%, there was little the corporations could do to directly enforce their edicts. The Martian digital democracy ground into gear, and furious discussions filled AI moderated chatrooms and algorithmically sorted message boards. After weeks of discussion the top voted comment that had emerged out of all the various layers of discourse, stated:
“Dear United Nations,
We did not ask to join your clubhouse of countries, we did not ask to be subject to your rules. In fact, we formed our government specifically to get out from under a bunch of your rules. We’re not going to follow them, regardless of whatever edicts or decrees you pass saying we have to. You have no authority on our planet. Your corporate lapdogs have no authority on our planet, and we reject your claims of jurisdiction over us. We are refugees of the tyranny of Earth, and we refuse to let you drag us kicking and screaming back into the dark ages of oligarchs and tyrants. This is a new age, one of automation, knowledge, free thought, and openness. You are not taking our planet from us, kindly go fuck yourselves, and have a lovely rest of your lives.
Love,
Mars”
The post received over 800,000 upvotes, representing nearly the total adult voting population of Mars, and was read by the Martian Ambassador to the UN general assembly aloud to the room in its entirety. The governments of Earth and the corporations they represented, reeled from the slap to the face, and immediately declared the Martian government a rogue state in defiance of International law. The reaction of the Martians was mocking, asking what the governments of Earth thought they were going to do about it. The UN arrested the Martian ambassador for collusion with a rogue state, and the Martians declared war in response.
It was initially a baseless threat. The Martians had no military to speak of, it was merely a way for them to reflect their frustrations with the breakdown of negotiations, few thought it would ever result in actual military action. Regular trade between the two worlds continued seemingly unabated, with over a thousand ships launched between the two worlds during the 2052 window. Their perspective on waging war changed rapidly when a fleet of ships from Earth arrived in 2053, having launched in secret, hidden amongst the commercial vessels. The fleet was composed of armed corporate paramilitaries, mercenaries and private operators, all armed with the latest and greatest of Earth military technology, modified specifically for operations on the red planet.
The fleet landed outside major population centers and stormed in to seize control. Many of the smaller installations and colonies gave in without struggle when rushed by the armored suit wearing paramilitaries, but in more populous areas, the colonists dug in hard. The Martian War of Independence had begun.
Sacra Mensa was seen as the priority target for the invading corporate forces, being the seat of the Martian government as well as the largest single colony on the surface. However, its high bluffs protected it from approach, and the colonists shot down the three ships that attempted to land directly on the Mesa with improvised rockets.
Death tolls on both sides began rising, but the colonists had a major numbers advantage on their invaders. As the Martians realized they were actually fighting a war, more and more Martian military production began to come online, and Martian militias rapidly formed to defend their colonies and homesteads.
The corporate invasion began to falter as Martian tanks started rolling off fabrication lines, and the power imbalance began to tilt. It took nearly a year to retake control of the Martian surface in its entirety, but by that point the Martians had started amassing the first generation of interplanetary warships in orbit of their world. The shallower gravity well of Mars made it easier to put bigger ships into orbit in greater numbers, and the wartime economy of Mars was almost entirely directed towards survival or military output in an unprecedented feat of economic unity.
By the time the next launch window approached, nearly two hundred brand new Martian warships crowded the red planet’s equatorial orbital plane. Following the footage of the invasion of Mars, the governments of Earth had grown reticent to engage with the Martians following the public backlash from the corporate backed invasions. The corporations themselves however, were still not ready to give up yet, and threw dozens more vessels filled with paramilitaries at Mars.
The Martians watched, waited, and when they finally witnessed the distant deployment of forces against them, held another vote and decided enough was enough. 62% of the population voted to attack earth in response, and demand a cessation of hostilities toward Mars in exchange for a cessation of hostilities toward Earth.
A third of the Martian fleet launched toward Earth, third launched toward the incoming corporate military vessels, and a third remained in orbit of Mars as a defensive screen. The Martians demanded the corporate ships stand down and turn back or face the consequences, and gave the UN until their ships arrived to figure out what to do. The various conflicting corporate and governmental forces comprising the United Nations argued back and forth over what to do about the Mars Situation. Many of the more powerful nations and corporate factions didn’t consider the new Martian military a real threat, and remained confident they could be forced back into the fold at gunpoint. In order to prove their point, all they had to do was stall peace talks and keep the argument going until their fleet arrived at Mars.
The second corporate invasion force was twice the size of the first, armed with weapons designed to be fired down from orbit as artillery support, as well as aerial drones designed to work in the thin Martian atmosphere and power armor for use in house to house fighting.
Their fleet was not however, designed to fight a battle with another fleet of ships in space. The Martian fleet was cobbled together in appearance and largely assumed to be no more than ferries for ground troops, not a threat that had to be warded off; desperate boarding actions were the most that was expected.
It thus came as a major shock when the Martian fleet engaged the UN forces in interplanetary space three months later, firing guided missiles from hundreds of thousands of kilometers away, and destroying the corporate invasion force in its entirety. Earth went into an uproar at the sudden turning of the tables, and the discussion regarding Mars grew more angry and muddied as a result.
In February of 2055, the two Martian fleets converged on Earth’s sphere of influence, settling into an orbit of the moon. Over one hundred warships formed a belt around the moon, their running lights glittering in the moon’s shadow. The small UN outpost on the moon was boarded and the crew were captured as prisoners of war.
Again, the Martians sued for recognition of their independence, broadcasting a plea for peace. The UN again argued over how to respond, and after another month of debate, declared that they did not negotiate with terrorists.
The direct electronic democracy on Mars churned, peace seeking factions formed and debated with factions that wanted to invade and topple the government of Earth to liberate it, suggestions for response ranged anywhere between ‘render the planet uninhabitable’ and ‘immediately sue for peace while we clearly have the upper hand.’ The fact that the UN continued to declare the Martian Socialist Republic illegitimate unless they submitted to corporate authority was lobbed back and forth like a beach ball as automated democratic systems tried to zero in on the solution space. In March of that year, a 600,000 upvote answer came to dominate the discourse, and after another week of talking, was transmitted down to the Earth.
“Dear United Nations,
We will keep destroying your fleets as you send them. Stop sending them. We want peace you dolts, stop forcing our hands. We will force yours harder.
Love,
Mars"
The UN response was swift and brutal, the governments of Earth fired hundreds of nuclear missiles at the Martian fleet in orbit of the moon. The Martian forces scattered, trying to outrun the missiles as they climbed out of Earth’s gravity well, but the much greater acceleration tolerance afforded by the nonliving missiles ensured they caught up to the ships hauling the fragile humans. After a week’s pursuit, the missiles finally caught up with their quarry as they attempted to loop back around and land on the Earth. Escape shuttles scattered by the hundred like seeds in the upper atmosphere, before the Martian warships vanished from orbit in nuclear starbursts. The Martians that survived the destruction of their fleet went to ground on Earth, and began a protracted guerrilla campaign against corporate shipyards and infrastructure. Earth and Mars swung apart once more on their orbits, and another two year buildup of arms began.
Second generation Martian warships began to crowd the red planet’s orbit once more, with the UN mirroring the Martian tactical doctrines and launching their own warships. The Martians were fed up with fighting though, and they were fed up with Earth. They decided it was time to send a message, and began changing the orbit of a 500 meter long nickel-iron asteroid. Powerful thrusters shifted the trajectory of the rock, swinging it around Mars and launching it back out of the sphere of influence on a retrograde heliocentric orbit that would send it looping around towards the Earth.
Mars transmitted a daily demand for peace, for the corporate military forces to stand down and cease their aggression against Mars, and still the buildup in Earth orbit continued. The Martians knew they had to force the issue, they couldn’t win a protracted struggle, Earth could in the end, simply outproduce them. Already three hundred corporate warships floated in a parking orbit around the Earth.
In October of 2056, the launch window opened from Earth once more and, the fleet of paramilitary warships launched themselves towards Mars. Mars issued their ultimatum: turn the fleet back now, or we start destroying your cities. The fleet continued onward towards Mars, and the Martian fleet launched towards it.
A few days later, the 500 meter long asteroid made a final course adjustment and came screaming at the Earth from interplanetary space. It slammed into the planet at 60 kilometers per second, perfectly striking the International Court of Justice in The Hague and carving out a ten kilometer wide crater where the Dutch city had once stood.
Earth accepted the peace offer the following day. Tensions and hostility from the two worlds as a result of the conflict would persist for over a century.
Chapter 13: Humans in Funny Suits
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